The long term goal of this research is to study homeostatic mechanisms that control the excitability of cortical interneurons. Tonically active GABA-A receptors can be a powerful regulator of homeostasis. The overall goal for the research presented in this proposal therefore is the expression and regulation of this inhibitory tonic current (l-Tonic) and these specialized GABA-A receptors. A combination of whole-cell patch-clamp slice electrophysiology, knockout mice, and immunocytochemistry techniques are employed to study tonic inhibition in layer 4 of the mouse somatosensory barrel cortex. There are two primary goals of this proposal. The first goal is to identify cell-type specific basal levels of and mechanisms behind this tonic inhibition. Our preliminary data suggests that two major inhibitory cell types (the regular spiking non pyramidal (RSNP) and the low threshold spiking (LTS)) are inhibited by large tonic currents, mediated at least in part by 6-subunit containing receptors. The second goal is to identify activity- level-dependent, homeostatic, changes in l-Tonic. Whisker plucking alters the level of activity in layer 4 barrel cortex. The second set of experiments proposed here examines the effects of this on excitability and tonic inhibition in cortical neurons. The experiments stemming from this application focus on a basic mechanism that controls the intrinsic plasticity of cortical interneurons and as such is applicable to a broad spectrum of disease states. We use a sensory system that allows us to study use-dependent reductions in cell excitability. Understanding the basic mechanisms that control excitability (e.g., homeostasis) will provide insight for understanding the developmental process of disease.